Technical Field
Methods and compositions are provided for treatment of disorders associated with aberrant adrenal cortex cell behavior.
Description of the Related Art
The adrenal gland is made up of two parts: the outer cortex in which certain hormones are produced, and the inner medulla which is part of the nervous system, wherein nervous system hormones are produced. The cortex is devoted to the synthesis of corticosteroid and androgen hormones. Specific cortical cells produce particular hormones including aldosterone, cortisol, and androgens such as androstenedione. Adrenocortical tumors originate in the cortex.
There are two main types of adrenal cortex tumors: adenomas which are benign and adrenocortical carcinoma which are malignant. Adenomas in many people produce no symptoms, but in some instances the tumors lead to excess hormones production. Adrenocortical carcinoma can produce the hormones cortisol, aldosterone, estrogen, or testosterone, as well as other hormones. Adrenocortical carcinomas (ACC) are rare, highly malignant tumors. In women the tumor often releases these hormones, which can lead to male characteristics. The excess hormones may or may not cause symptoms. In general, adenomas are treated by removal of the adrenal gland or with therapeutic intervention. Likewise, adrenocortical carcinomas can lead to hormone production that can cause noticeable body changes such as weight gain, fluid build-up, early puberty in children, or excess facial or body hair in women. While the cause is unknown, adrenocortical carcinoma is most common in children younger than 5 and adults in their 30s and 40s. Adrenocortical carcinoma may be linked to a cancer syndrome that is passed down through families (inherited). Both men and women can develop this tumor.
Various stages of adrenocortical carcinomas are defined as follows. Stage I is cancer of the adrenal gland that is smaller than 5 centimeters (smaller than 2 inches) and is found in the adrenal gland only. Stage II is cancer of the adrenal gland that is larger than 5 centimeters (about 2 inches) and is found in the adrenal gland only. Stage III is cancer of the adrenal gland that has spread into fat and lymph nodes near the adrenal gland. Stage IV is cancer of the adrenal gland that has spread to fat or organs and to lymph nodes near the adrenal gland or to other parts of the body, such as lungs, liver, bones, and abdomen.
While the understanding of the disease has advanced with the advent of modern molecular techniques, the prognosis of patients with advanced disease, who represent about half of the diagnoses, remains dismal. Targeted therapies are in clinical development, but whether they will yield breakthroughs in the management of the disease is yet unknown (Hammer, G. D. and T. Else, eds., Adrenocortical Carcinoma, Basic Science and Clinical Concepts, 2011, New York: Springer).
The sole FDA-approved therapeutic agent for ACC is mitotane (o.p′-DDD), a derivative of the insecticide DDT, discovered in 1950s, when it was found to destroy the adrenal cortex of dogs. Despite half a century of use, its molecular mechanism remains unclear. The drug requires chemical transformation into an active, free radical form, which then induces lipid peroxidation and cell death. Mitotane also suppresses steroidogenesis and inhibits other cytochrome P450-class enzymes (Id.).
Whereas mitotane is widely used for the treatment of ACC, it has increased progression-free survival in only one-quarter to one-third of patients. For the patients that derive a therapeutic benefit, the effect is transient, delaying disease progression by an average of five months (Id.). Mitotane has numerous problems as a therapeutic agent, making its use difficult, and requiring close monitoring of patients. These problems include:                Severe side effects: practically all patients experience gastrointestinal dysfunctions and CNS symptoms. Mitotane causes elevated cholesterol and triglycerides, lowered thyroid hormone function, elevated liver enzymes, and leukopenia (Id.);        Narrow therapeutic window: 14 mg/l is required for therapeutic benefit, 20 mg/l is toxic (Hermsen, I. G., et al., J. Clin. Endocrinol. Metab., 96(6):1844-51, 2011); and        Poor ADME properties: The dose of mitotane must be frequently adjusted to achieve an adequate rate of loading without causing side effects. Even with a high drug intake by patients, it takes several months to reach target therapeutic blood levels. The drug accumulates in fat tissue, with an elimination half-life of months. Mitotane interferes with the metabolism of other drugs, making medical management of the many debilitating symptoms and additional chemotherapy of ACC patients challenging (Kroiss, M., et al., Clin. Endocrinol. (Oxf) 75(5):585-91, 2011; van Erp, N. P, Eur. J. Endocrinol. 164(4):621-6, 2011).        
Because of the multiple limitations of mitotane as a therapy for ACC, a replacement with better efficacy and safety profile is highly desirable for the management of this deadly disease.